Differential expression of PPAR isoforms in streptozotocin induced model of sporadic alzheimer's disease in zebrafish.
BACKGROUND: Sporadic Alzheimer's Disease (sAD) is a multifactorial neurodegenerative disorder in which metabolic dysfunctions and central insulin resistance are recognized as key pathogenic drivers accompanied by amyloid and tau pathology. Effective disease-modifying therapies remain elusive, representing a major global public health concern. Peroxisome proliferator-activated receptors (PPARs) have emerged as promising therapeutic targets due to their roles in regulating neuroinflammation, lipid metabolism and insulin sensitivity. Despite extensive studies highlighting the distinct role of PPAR isoforms in neurodegeneration, their involvement in sAD pathology remains unexplored. METHODS: The role of PPARs was evaluated in streptozotocin (STZ) model of sAD. STZ was administered intracerebroventricularly at a dose of 5 mg/kg for 7 days. The cognitive functions and expression of PPAR isoforms and its downstream targets were investigated in adult zebrafish. RESULTS: STZ-treated zebrafish exhibited significant cognitive impairment with decreased preference for the novel object indicating working memory deficits. Molecular analysis revealed isoform-specific modulation of PPARs. PPARα was upregulated, whereas its downstream targets (acox1, cpt1, map3k8) were downregulated suggesting impaired transcriptional activation. PPARγ, PPARβ/δ and their targets were significantly downregulated at both transcript and protein levels suggesting suppression of their neuroprotective functions. Immunofluorescence revealed distinct spatial localization patterns; PPARα was prominent in telencephalon and optic tectum; PPARγ showed punctate nuclear expression in preoptic area; and PPARβ/δ displayed diffuse nuclear staining in diencephalon. CONCLUSIONS: These findings demonstrate that STZ-induced cognitive deficits are accompanied by region-specific dysregulation in expression of PPAR isoforms suggesting that PPAR modulation may be a therapeutic strategy to prevent sAD pathogenesis.